In accordance with the mission of the NIEHS, understanding how environment influences human disease etiology and progression, this project will examine the contribution of two high-usage pesticides to general neurotoxicity as well as Parkinson's disease (PD). Numerous reports suggest a link between PD and agricultural environments and/or pesticide usage. Other data indicate that exposure to manganese (Mn) also may be linked to disease onset. Interestingly, many agrochemicals, as well as Mn, impair mitochondrial respiration, resulting in an insufficient quantity of energy production required for cells survival. Furthermore, mitochondrial dysfunction is present in various cell populations in PD patients. The long-term goal of this project is to understand the mechanisms through which pesticides may contribute to cell death in brain regions associate with to PD. Using the nematode Caenorhabditis elegans (C. elegans), the following hypothesis will be tested: Exposure to the popular pesticides Mancozeb (MZ) and TouchDown (TD) leads to neuronal degeneration via mitochondrial inhibition and/or increased oxidative stress. Additionally, it is hypothesized that these pesticides may enter vulnerable neuron through uptake by specific neurotransmitter transporters. These hypotheses will be tested through three specific aims: (1) to establish which mitochondrial complexes are inhibited; (2) to discover the specific reactive oxygen species (ROS) increased following exposure to MZ and/or TD; and (3) to determine if MZ and TD enter neurons through individual neurotransmitter or metal transporters. In order to monitor neurodegeneration, C. elegans with neuronal populations tagged with green fluorescent protein (GFP) will be exposed to varying concentrations of MZ or TD. This will be followed by treatment with various chemical reporters to determine whether mitochondrial function is compromised. Subsequent studies will involve pretreatment of worms with specific neurotransmitter transporter antagonists to determine if assess whether degeneration is decreased following subsequent exposure to MZ or TD. Results from these novel studies will further our understanding of neurotoxic effects related to pesticide exposure. Additionally, this work will provide evidence related to mechanisms involved in intracellular transport of glyphosate-containing herbicides (i.e., TD, RoundUP), or manganese-containing fungicides (i.e., MZ, maneb). It is anticipated that these data will further our understanding not only of general pesticide neurotoxicity, but also of mechanisms through which environmental toxicants may contribute the etiology of idiopathic PD. PUBLIC HEALTH RELEVANCE: These studies are particularly timely and relevant to public health because of the link between Parkinson's disease (PD), the second most-common neurodegenerative disease in the United States, and pesticide exposure. Use of glyphosate-containing herbicides (i.e., RoundUp and TouchDown) is increasing exponentially in the general public and the agricultural community, while Mancozeb, a manganese-containing fungicide, is gaining increased market shares. These pesticides are suspected mitochondrial inhibitors, an observation commonly documented in various cell populations in PD patients.